2-(1H-indol-3-yl)-2-oxo-acetic acid amides with antitumor activity

ABSTRACT

2-(1H-Indol-3-yl)-2-oxo-acetamide derivatives of formula (I) having antitumor activity in particular against solid tumors, specifically colon and lung tumors.

CROSS REFERENCE TO RELATED APPLICATION

This application is a 35 USC 271 National Phase Entry Application fromPCT/EP01/08075, filed Jul. 12, 2001, and designating the U.S.

The present invention relates to 2-(1H-indol-3-yl)-2-oxo-acetamidederivatives having antitumor activity, in particular against solidtumors, specifically colon and lung tumors.

The carcinoma of the colon and rectum is a very common tumor in Westerncountries, in that it has an incidence of about 421,000 new cases eachyear in the world and is second only to lung and breast tumors as causeof death.

The percentage of patients which can be treated surgically is about45–50%, the remaining patients being treated with combined chemotherapy,to obtain a complete remission percentage not above 5%.

Tumors of the colon and rectum are usually refractory or poorlysensitive to chemotherapy available at present and the only effectiveagent to some extent against this type of cancer is 5-fluorouracil.

Unfortunately no therapeutical alternatives exist at present in case offailure of combined chemotherapy substantially based on 5-FU.

Therefore there is a remarkable need for novel drugs active against thistype of tumors.

WO 98/09946 in the name of Asta Medica discloses indole-3-glyoxylamidederivatives. The compounds are substituted at the amido nitrogen atomwith aromatic, pyridyl and aryl/heteroaryl substituted pyperazinylresidues and reportedly have antiasthmatic, antiallergic,immunosuppressive and immunomodulating activities. WO 99/51224 in thename of Asta Medica discloses the use of said compounds as antitumoragents as well as novel N-oxides of said products with antitumoractivity.

It has now been found that 2-(1H-indol-3-yl)-2-oxo-acetic acid amideswith heterocyclic amines have marked antitumor activity, particularlyagainst human solid tumors.

The compounds of the invention can be represented by the general formula(I):

wherein:

-   -   HET is a four to seven membered heterocyclic group, aromatic or        non aromatic, containing one or more nitrogen, oxygen or sulfur        atoms in one or more heterocyclic rings and optionally        substituted on the carbon atoms with halogens, alkyl, hydroxy,        alkoxycarbonyl, carboxy, cyano groups or, on the nitrogen atoms,        with alkyl, aryl, arylalkyl groups or with oxygen atoms to form        N-oxides;        and optionally fused to one or two aryl or cycloalkyl groups, in        their turn optionally substituted with halogens, alkyl, hydroxy,        alkoxycarbonyl, carboxy, cyano groups;    -   R₃ is hydrogen, C₁–C₄ alkyl, aralkyl, optionally substituted        phenyl;    -   R₄ is straight or branched C₁–C₈ alkyl, C₅–C₆ cycloalkyl;        aralkyl; heteroaralkyl;    -   X represents one or more groups, up to four, independently        selected from hydrogen, C₁–C₆ alkyl, hydroxy, C₁–C₄ alkoxy,        C₁–C₃ haloalkoxy, phenoxy, aralkoxy, C₁–C₃ acyloxy, amino, C₁–C₃        alkylamino, C₁–C₃-acylamino, C₁–C₃-alkylsulfonylamino,        aroylamino, halogen, nitro, cyano, trifluoromethyl, carboxy,        C₁–C₃ alkoxycarbonyl, a R_(a)R_(b)N(CH₂)nC(═O)— group where        R_(a) and R_(b) are independently hydrogen, C₁–C₃-alkyl or R_(a)        and R_(b) together with the nitrogen atom they are linked to        form a pyrrolidino, piperidino, piperazino or morpholino ring        and n=0 or an integer 2 to 4, sulfonyl, mercapto,        C₁–C₄-alkylthio, C₁–C₄-alkylsulfonyl, C₁–C₄-alkylsulfinyl,        aminosulfonyl, C₁–C₃-alkylaminosulfonyl;        with the proviso that HET is different from aryl/heteroaryl        substituted piperazine, or pyridine or pyridine-N-oxide.

The invention also relates to the salts of compounds of formula (I)obtainable by reacting non toxic acids or bases with the ionizablegroups present in the compounds (I), and the tautomeric mixtures of thecompounds of formula (I).

Examples of four to seven membered heterocyclic rings containing one ormore nitrogen, oxygen or sulfur atoms are: pyrrole, furan, thiophene,pyrazole, thiazole, indole, oxazole, imidazole, isothiazole, isoxazole,1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole,1,2,5-oxadiazole, 1,2,5-thiadiazole, (1,3,4-thiadiazole, tetrazole,pyrimidine, pyridazine, pyrazine, 1,2,4-triazine, benzofuran, indazole,carbazole, benzoxazole, benzimidazole, benzothiazole, benzotriazole,quinoline, isoquinoline, cinnoline, quinoxaline, quinazoline,phthalazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, purine,pteridine.

Optionally substituted phenyl preferably means phenyl, 4-methylphenyl,2,4-dimethoxy-phenyl, 4-methoxy-phenyl, 4-nitro-phenyl, 3-chlorophenyl,4-hydroxyphenyl, 3,5-dimethoxy-4-hydroxy-phenyl, 3-cyano-phenyl,2-hydroxyphenyl, 2-carboxyphenyl.

Aralkyl preferably means benzyl, phenethyl, naphthylmethyl,biphenylmethyl, optionally substituted with one or more halogens,trifluoromethyl, nitro, cyano, methylsulfonyl, tert-butyl groups.

Heteroaralkyl preferably means pyridylmethyl.

HET is preferably a five or six membered heterocyclic ring selected fromthe group consisting of furan, pyrrole, thiophene, oxazole, isoxazole,thiazole, isothiazole, pyrazole, imidazole, 1,2,3-triazole,1,2,4-triazole, 1,3,5-triazole, 1,3,4-oxadiazole, 1,2,4-oxadiazole,1,2,5-oxadiazole, 1,2,5-thiadiazole, thiadiazole, 1,3,5-thiadiazole,1,2,3-triazine, 1,2,4-triazine, tetrazole, pyrimidine, pyrazine,pyridazine. Particularly preferred are pyrazole, isoxazole, thiazole,1,3,5-thiadiazole.

R₃ is preferably hydrogen or methyl.

R₄ is preferably methyl; benzyl substituted on the benzene ring with oneor more groups selected from methyl, fluorine, chlorine, bromine,hydroxy, acetoxy, methoxy, methoxycarbonyl, ethoxycarbonyl,trifluoromethoxy, trifluoromethyl, cyano, nitro, amino, acetylamino,methylsulfonylamino, methylmercapto, methysulfinyl, methylsulfonyl,phenyl; α-naphthylmethyl, β-naphthylmethyl; 4-pyridylmethyl;4-pyridylmethyl-N oxide.

X is preferably methyl, ethyl, fluorine, chlorine, bromine, hydroxy,acetoxy, methoxy, phenoxy, trifluoromethoxy, trifluoromethyl, cyano,nitro, amino, acetylamino, methylsulfonylamino, methylmercapto,methysulfinyl, methylsulfonyl.

The compounds of the invention can be prepared by reacting the compoundsof formula (II)

in which R₃, and R₄ and X are as defined above,with a compound of formula (III)H₂N-HET  (III)in which HET is as defined above.

The reaction is carried out in a solvent such as ethyl ether, isopropylether, methyl-tert-butyl ether, tetrahydrofuran, dioxane,1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, toluene,dimethylformamide, dimethylacetamide, dimethylsulfoxide, at atemperature ranging from 0° C. to the reflux temperature of the solvent,and using 1 to 3 molar equivalents of compounds of formula (III),optionally operating in the presence of at least one molar equivalent ofan acid-binding agent such as a tertiary organic base, for exampletriethylamine or diisopropylethylamine, or in the presence of aninorganic base such as alkali or alkaline-earth metal carbonates orbicarbonates.

The reaction is preferably carried out in an ether solvent such as ethylether, THF, 1,2-dimethoxyethane, at a temperature ranging from roomtemperature to 80° C., in the presence of potassium carbonate.

The resulting compounds of formula (I) can subsequently be transformedinto other compounds of formula (I) according to the proceduresconventionally used for the transformation of functional groups, such asreactions of hydrolysis of ester groups, esterifications of carboxylicacids, amidations and the like. For example, when in compounds offormula (II) the groups X and R₄ contain substituents which interferewith the reaction of the compounds of formula (II) with the compounds offormula (III), suitable protective groups will be used, which will besubsequently removed according to conventional methods.

Compounds of formula (II) are obtained by reacting the compounds offormula (IV)

in which X, R₃ and R₄ are as defined above, with oxalyl chloride.

The reaction is generally carried out in a solvent such as ethyl ether,isopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane,dichloromethane, at a temperature ranging from −10° C. to 25° C. andusing one to two molar equivalents of oxalyl chloride. The reaction ispreferably conducted at a temperature from 0° C. to 25° C. in ethylether or in tetrahydrofuran, using a slight excess (1.2 molarequivalents) of oxalyl chloride. The reaction is generally completedwithin 3 hours.

Compounds of formula (IV) are obtained by reacting the indoles offormula (V)

wherein X and R₃ are as defined above, with halides of formula R₄-Hal(VI), wherein R4 is as defined above and Hal is preferably chlorine orbromine, in the presence of acid-binding agents.

The reaction is generally carried out using an equimolar amount or aslight excess of halide (VI), in a protic, aprotic dipolar or apolarsolvent such as ethanol, isopropanol, tert-butanol, tetrahydrofuran,dioxane, dimethylsulfoxide, dimethylformamide, dimethylacetamide,N-methylpyirrolidinone, acetonitrile, in the presence of an alkali metalor alkaline-earth hydroxide or alkoxide or hydride such as sodiumhydroxide, sodium hydride, potassium tert-butoxide. Temperaturegenerally ranges from 0° C. to the reflux temperature of the solvent,for a time ranging from 30′ to 24 hours. The reaction is preferablyeffected in dimethylsulfoxide in the presence of an equimolar amount ofsodium hydride compared with compounds (V), operating at 0–25° C. forthe reaction of compounds (V) with sodium hydride, followed by additionof compounds (VI) and heating to 50–70° C. The reaction is generallycompleted within three hours.

Compounds of formula (V) and (VI) are known or may be prepared withknown methods, and many of them are commercially available.

Compounds of formula (III) are known or may be prepared with knownmethods.

The compounds according to the invention were pharmacologically testedagainst human tumor cell lines: HT 29 (colon carcinoma), PC 3 (prostatecarcinoma), H 460M (lung carcinoma), MKN-45 (gastric carcinoma). Cellswere incubated for 144 hour with the tested compound, then cytotoxicitywas determined using the MTT test (Mosman, T. “Rapid Colorimetric Assayfor Cellular Growth and Survival: Application to Proliferation andCytotoxicity Assay”; J. Immunolog. Methods, (1983), 65, 66; Green, L.M., “Rapid Colorimetric Assay for Cell Viability; Application to theQuantitation of Cytotoxic and Growth Inhibitory Lymphokines”, J.Immunol. Methods, (1984), 70, 257–268).

The obtained data showed that the compounds of the present inventionhave a marked activity against solid tumors, in particular colon andlung tumors.

The compounds of the invention can be administered in doses ranging from0.01 mg to 1 g/Kg body weight daily. A preferred administrationprocedure is that using a dosage from about 1 mg to about 500 mg/Kg bodyweight daily, using such unitary doses as to administer in 24 hours fromabout 70 mg to about 3.5 g of the active substance to a patient of about70 Kg. Such administration procedure can be adjusted to obtain a bettertherapeutical effect. For example, doses can be adjusted according tothe therapeutical conditions of the patient.

The active compounds of the invention can be administered through theoral, intravenous, intramuscular or subcutaneous routes.

The compounds of the invention, when administered, according to wellknown therapeutical procedures, in combination with other agents used toinduce the regression of tumors, synergistically enhance the antitumoreffects of said compounds. Examples of the compounds which can be usedin combination with the compounds of the invention are cisplatin,carboplatin, doxorubicin, topotecan, taxol, taxotere, vincristine,5-fluorouracil.

The pharmaceutical compositions of the invention contain therapeuticallyeffective amounts of at least one compound of the invention in mixturewith excipients compatible with the pharmaceutical use.

The compositions for the oral route generally comprise an inert diluentor an edible carrier and can be in the form of gelatin capsules ortablets. Other possible oral administration forms are capsules, pills,elixirs, suspensions or syrups.

Tablets, pills, capsules and similar compositions can contain thefollowing ingredients (in addition to the active compound): a ligand,such as microcrystalline cellulose, tragacanth or gelatin; a carriersuch as starch or lactose; a disintegrant such as alginic acid,primogel, maize starch and the like; a lubricant such as magnesiumstearate; a fluidifying agent such as colloidal silicon dioxide; asweetener such as saccharose or saccharin or a flavoring agent such asmint flavor, methyl salicylate or orange flavor. When the selectedcomposition is in the form of capsules, it also can contain a liquidcarrier such as a fat oil. Other compositions can contain variousmaterials, for example coating agents (for tablets and pills) such assugar or shellac. The material used in the preparation of thecompositions should be pharmaceutically pure and not toxic at the useddosages.

For the pharmaceutical compositions for the parenteral administration,the active ingredient can be included in solutions or suspensions, whichcan further contain the following components: a sterile diluent such aswater for injections, saline solution, oil, polyethylene glycol,glycerin, propylene glycol or other synthetic solvents; antibacterialssuch as benzyl alcohol; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylenediaminetetraacetic acid;buffering agents such as acetates, citrates or phosphates and tonicityagents, such as sodium chloride or dextrose. The parenteral preparationscan be contained in ampoules, single-dose syringes, glass or plasticvials.

The present invention will be further described by the followingexamples.

Preparation 1: 1-(2,4,6-trimethylbenzyl)indole

A solution of indole (1.185 g) in dry DMSO (3 ml) is dropped into asuspension of sodium hydride (60% suspension in mineral oil; 0.44 g) indry DMSO (10 ml). After two hours, the resulting solution is added witha solution of 2,4,6-trimethylbenzyl chloride (1.9 g) in dry DMSO (2 ml)and the reaction mixture is heated at 60° C. for 6 h. After a night atroom temperature, the reaction mixture is poured into water (250 ml) andextracted with ethyl acetate, then dried (Na₂SO₄) The drying agent isfiltered off and the solvent is evaporated off under reduced pressure.The resulting residue is purified by column chromatography (silica gel;eluent n-hexane/AcOEt 9/1), to obtain 2.2 g of1-(2,4,6-trimethylbenzyl)indole.

m.p. 79–81° C.

Preparation 2: 1-(n-octyl)indole

A solution of indole (1.0 g) in dry DMSO (1 ml) is dropped into asuspension of sodium hydride (60% suspension in mineral oil; 0.37 g) indry DMSO (20 ml), heating to 60° C. for 1 h. After cooling at roomtemperature, the resulting solution is added dropwise with a solution ofn-octyl bromide (2.82 ml) in dry DMSO (2.8 ml). After a night at roomtemperature, the reaction mixture is poured into water (200 ml) andextracted with ethyl acetate (2×50 ml). The combined organic phases arewashed with a NaCl saturated solution, dried and evaporated to dryness.The resulting residue is purified by column chromatography (silica gel;eluent n-hexane) to obtain 1.86 g of 1-(n-octyl)indole as oil.

Preparation 3: 1-substituted Indoles

Using the procedures described in preparations 1 and 2, the following1-substituted indoles are prepared starting from the suitable indolesand halides:

-   1-(4-cyanobenzyl)indole, oil;-   1-(4-chlorobenzyl)-5-chloroindole, oil;-   1-(4-chlorobenzyl)-6-chloroindole, oil;-   1-(4-chlorobenzyl)-2-methylindole, oil;-   1-(4-chlorobenzyl)-5-nitroindole, m.p. 135–137° C.;-   1-(4-chlorobenzyl)-6-fluoroindole, oil;-   1-[4-(methylsulfonyl)benzyl]-5-chloroindole, m.p. 133–135° C.;-   1-(4-chlorobenzyl)-5-methoxyindole, oil;-   1-(3-chlorobenzyl)indole, oil;-   1-(4-fluorobenzyl)indole, oil;-   1-(β-naphthylmethyl)indole, m.p. 106–108° C.;-   1-(4-biphenylmethyl)indole, m.p. 130–133° C.;-   1-(4-methoxybenzyl)indole, oil;-   1-benzylindole, oil;-   1-(4-chlorobenzyl)indole, oil;-   1-methylindole, oil;-   5-chloro-1-(4-chlorobenzyl)-2-methylindole;-   5-methoxy-1-(4-chlorobenzyl)-2-methylindole;-   1-(4-chlorobenzyl)-2,5-dimethylindole;-   4-chloro-1-(4-chlorobenzyl)indole;-   4-acetoxy-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-4-methylindole;-   1-(4-chlorobenzyl)-5-cyanoindole;-   5-bromo-1-(4-chlorobenzyl)indole;-   5,6-dimethoxy-1-(4-chlorobenzyl)indole;-   5-benzyloxy-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-5-(methoxycarbonyl)indole;-   5-acetylamino-1-(4-chlorobenzyl)indole;-   5-methanesulfonylamino-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-5-methylindole;-   1-(4-chlorobenzyl)-6-methylindole;-   1-(4-chlorobenzyl)-7-nitroindole;-   1-(4-chlorobenzyl)-7-methylindole;-   1-(4-chlorobenzyl)-4-methoxyindole;-   1-(4-chlorobenzyl)-4-(ethoxycarbonyl)indole;-   1-(4-chlorobenzyl)-4-nitroindole;-   4-acetylamino-1-(4-chlorobenzyl)indole;-   6-cyano-1-(4-chlorobenzyl)indole;-   5,7-dimethoxy-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-2-phenylindole;-   1-(4-chlorobenzyl)-2-phenyl-5-methylindole;-   1-(4-chlorobenzyl)-2,7-dimethylindole;-   1-(4-chlorobenzyl)-6-methoxyindole;-   2-(4-chlorophenyl)-1-ethylindole;-   5-benzyloxy-1-(4-chlorobenzyl)-6-methoxyindole;-   7-benzyloxy-1-(4-chlorobenzyl)indole;-   5-benzyloxy-1-(4-chlorobenzyl)-6-methoxyindole;-   1-(4-chlorobenzyl)-5, 6-methylenedioxyindole;-   1-(4-chlorobenzyl)-2-(4-chlorophenyl)indole;-   4-benzyloxy-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-7-methoxyindole;-   1-(4-chlorobenzyl)-4, 5, 6-trimethoxyindole;-   1-(4-chlorobenzyl)-2-ethylindole;-   1-(4-chlorobenzyl)-6-nitroindole;-   6-benzyloxy-1-(4-chlorobenzyl)indole;-   4-fluoro-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-2-(4-fluorophenyl)indole;-   1-(4-chlorobenzyl)-2-(3-chloro-4-fluorophenyl)indole;-   1-(4-chlorobenzyl)-2-(3,4-difluorophenyl)indole;-   5-acetylamino-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-2-methyl-5-nitroindole;-   1-(4-chlorobenzyl)-2-(4-fluorophenyl)indole;-   2-(2-acetylaminophenyl)-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-7-ethylindole;-   6-acetoxy-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-4,7-dimethoxyindole;-   1-(4-chlorobenzyl)-4-methoxycarbonylindole;-   4-(4-chlorobenzoylamino)-1-(4-chlorobenzyl)indole;-   1-(4-chlorobenzyl)-6-methoxycarbonylindole;-   1-(4-chlorobenzyl)-7-methoxycarbonylindole;-   1-(4-chlorobenzyl)-6-(2-dimethylaminoethylaminocarbonyl)indole;-   1-(4-chlorobenzyl)-5-iodoindole;-   1-(n-butyl)indole;-   1-(4-chlorobenzyl)-4,5,6,7-tetrafluoroindole;-   1-(4-chlorobenzyl)-6-trifluoromethylindole;-   4-chloro-1-(4-chlorobenzyl)-6-methoxyindole;-   6-chloro-1-(4-chlorobenzyl)-4-methoxyindole;-   1-(4-chlorobenzyl)-5-phenoxyindole;-   1-(4-chlorobenzyl)-2-(2-chlorophenyl)indole;-   1-(4-chlorobenzyl)-5,6-methylenedioxyindole;-   1-(2-bromobenzyl)indole;-   1-(3-bromobenzyl)indole;-   1-(4-bromobenzyl)indole;-   1-(4-bromobenzyl)-6-methylindole;-   1-(2-methylbenzyl)indole;-   1-(3-methylbenzyl)indole;-   1-(4-methylbenzyl)indole;-   1-(4-methylbenzyl)-6-fluoroindole;-   1-(4-tert-butylbenzyl)indole;-   1-(4-tert-butylbenzyl)-6-methoxyindole;-   1-(2,3,4,5,5-pentafluorobenzyl)indole;-   1-(2-fluorobenzyl)indole;-   1-(2,6-difluorobenzyl)indole;-   1-(3-fluorobenzyl)indole;-   1-(3-fluorobenzyl)-5-bromoindole;-   1-(4-fluorobenzyl)indole;-   1-(3-trifluoromethylbenzyl)-6-nitroindole;-   1-(4-trifluoromethylbenzyl)indole;-   1-(4-trifluoromethylbenzyl)-5-methanesulfonylaminoindole;-   1-(2-chlorobenzyl)indole;-   1-(2,6-dichlorobenzyl)indole;-   1-(3-chlorobenzyl)indole;-   1-(2-cyanobenzyl)indole;-   1-(3-cyanobenzyl)indole;-   1-(4-cyanobenzyl)-6-fluoroindole;-   1-(4-methoxycarbonylbenzyl)indole;-   1-(4-methoxycarbonylbenzyl)-6-fluoroindole;-   1-(2-nitrobenzyl)indole;-   1-(3-nitrobenzyl)indole;-   1-(2-methoxy-5-nitrobenzyl)indole;-   1-(4-nitrobenzyl)indole;-   1-(3,4-difluorobenzyl)indole;-   1-(3,4-difluorobenzyl)-6-methoxyindole;-   1-(2,5-difluorobenzyl)indole;-   1-(3,5-bis(trifluoromethyl)benzyl)indole;-   1-(3,5-difluorobenzyl)indole;-   1-(2,4-bis(trifluoromethyl)benzyl)indole;-   1-(4-(methoxycarbonylmethyl)benzyl)indole;-   1-(2,4-difluorobenzyl)indole;-   1-(3,5-dimethylbenzyl)indole;-   1-(2-trifluoromethylbenzyl)indole;-   1-(2-chloro-6-fluorobenzyl)indole;-   1-(3,4-dichlorobenzyl)indole;-   1-(3,4-dichlorobenzyl)-6-fluoroindole;-   1-(3,4-dichlorobenzyl)-6-methylindole;-   1-(2-bromo-5-fluorobenzyl)indole;-   1-(2-fluoro-3-methylbenzyl)indole;-   1-(2,3-difluorobenzyl)indole;-   1-(3-chloro-2-fluorobenzyl)indole;-   1-(3-(methoxycarbonyl)benzyl)indole;-   1-(3,5-dibromobenzyl)indole;-   1-(4-fluoro-2-(trifluoromethyl)benzyl)indole;-   1-(2,3,6-trifluorobenzyl)indole;-   1-(2,4,5-trifluorobenzyl)indole;-   1-(2,4, 6-trifluorobenzyl)indole;-   1-(2,3,4-trifluorobenzyl)indole;-   1-(4-trifluoromethoxybenzyl)indole;-   1-(4-trifluoromethoxybenzyl)-6-carbomethoxyindole;-   1-(3-trifluoromethoxybenzyl)indole;-   1-(2-biphenylmethyl)indole;-   1-(4-difluoromethoxybenzyl)indole;-   1-(3,4-dimethoxy-6-nitrobenzyl)indole;-   1-(3-methoxybenzyl)indole;-   1-(2-chloro-4-fluorobenzyl)indole;-   1-(2,5-dichlorobenzyl)indole;-   1-(4-fluorobenzyl)-4-chloroindole;-   1-(4-fluorobenzyl)-5-chloroindole;-   1-(4-fluorobenzyl)-6-chloroindole;-   1-(4-fluorobenzyl)-2-methylindole;-   1-(4-fluorobenzyl)-5-nitroindole;-   1-(4-fluorobenzyl)-6-fluoroindole;-   1-[4-fluorobenzyl]-5-chloroindole;-   1-(4-fluorobenzyl)-5-methoxyindole;-   1-(4-fluorobenzyl)-4-methylindole;-   1-(4-fluorobenzyl)-5-methylindole;-   1-(4-fluorobenzyl)-6-methylindole;-   1-(4-fluorobenzyl)-7-methylindole;-   1-(4-fluorobenzyl)-5,6-methylenedioxyindole;-   1-(3-chlorobenzyl)-5-cyanoindole;-   1-(4-biphenylmethyl)-6-carbomethoxyindole;-   1-(4-methoxybenzyl)-4-chloroindole;-   5-acetylamino-1-benzylindole;-   6-fluoro-1-[(4-methylsulfonyl)benzyl]indole;-   1-methyl-6-methoxyindole;-   5-chloro-1-(4-methoxybenzyl)-2-methylindole;-   1-(4-pyridylmethyl)indole;-   1-(4-pyridylmethyl)-6-chloroindole.

Preparation 4: 2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetylChloride

A solution of 1-(4-chlorobenzyl)-1H-indole (2.0 g) in dry ethyl ether (5ml) kept under stirring and cooled at 0° C. is dropwise added with asolution of oxalyl chloride (0.85 ml) in dry ethyl ether (2 ml). Aftercompletion of the addition, the mixture is left at room temperature for2h. The separated solid is recovered by filtration, washed with dryethyl ether and dried under vacuum at 40° C. to give2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride (1.64 g).

m.p. 151–153° C.

¹H-NMR (CHCl₃-d3, ppm): 5.43 (s, 2H); 7.12 (d, 2H); 7.25–7.45 (m, 5H);8.25 (s, 1H); 8.43 (m, 1H).

The following products were prepared analogously:

-   2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(3-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(2-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(4-bromobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(4-cyanobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(3-nitrobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-(3,4-difluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride;-   2-(1-benzyl-1H-indol-3-yl)-2-oxo-acetyl chloride.

EXAMPLE 1N-(1,3,4-thiadiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide

A solution of 2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetyl chloride(318 mg) in dry 1,2-dimethoxyethane (5 ml) is added dropwise to asuspension of 2-amino-1,3,4-thiadiazole (91 mg) and dry, ground K₂CO₃(138 mg) in 5 ml of 1,2-dimethoxyethane, operating at room temperature.The reaction mixture is left under stirring for 12 hours then pouredinto water (60 ml). The resulting suspension is stirred for 30 minutes.The precipitate is filtered off and suspended in methanol (10 ml) understirring for 30 minutes. The solid is recovered by filtration and driedto giveN-(1,3,4-thiadiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide(168 mg).

m.p. 218–220° C.

¹H-NMR (DMSO-d6, ppm): 5.65 (s, 2H); 7.10–7.25 (m, 2H); 7.25–7.50 (m,4H); 7.65 (m, 1H); 8.25 (m, 1H); 8.95 (s, 1H); 9.35 (s, 1H); 13.30 (brs, 1H).

Elemental Analysis

% calculated for C19H13FN4O2S:

C=59.99, H=3.44, N=14.73, F=4.99

% found:

C=59.96, H=3.52, N=14.45, F=4.85.

EXAMPLE 2N-(thiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide

A solution of 1-(4-fluorobenzyl)indole (0.30 g) in ethyl ether (5 ml) isadded dropwise with a solution of oxalyl chloride (0.177 ml) in ethylether (10 ml). After one hour the reaction mixture is evaporated todryness and the residue is taken up into 1,2-dimethoxyethane (20 ml).The solution is added with dry, ground K₂CO₃ (0.183 g), then with2-aminothiazole (0.119 g). The reaction mixture is stirred at roomtemperature for 2 hours, then poured into water (100 ml) and stirred fora further hour. The separated solid is recovered by filtration andsuspended for an hour under stirring in methanol (10 ml). The product isfiltered off and dried to giveN-(thiazol-2-yl)-2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide(0.36 g).

m.p. 233–237° C.

¹H-NMR (DMSO-d6, ppm): 5.62 (s, 2H); 7.10–7.25 (m, 2H); 7.25–7.45 (m,5H); 7.60 (2m, 2H); 8.28 (m, 1H); 8.97 (s, 1H); 12.70 (br s, 1H).

Elemental Analysis

% calculated for C₂₀H₁₄FN₃O₂S:

C=63.31, H=3.72, N=11.08, F=5.00, S=8.45

% found:

C=63.21, H=3.70. N=10.81, F=4.86, S=8.20.

EXAMPLE 3

Using the procedures described in examples 1 and 2 and the suitable1-substituted indoles of preparations 1–3 or(1H-indol-3-yl)-2-oxo-acetyl chlorides of preparation 4 as startingmaterials, the following products were prepared:

2-(1-(4-fluorobenzyl)-1H-indol-3-yl)-N-(isoxazol-3-yl)-2-oxo-acetamide

m.p. 180–183° C.

¹H-NMR (DMSO-d6, ppm): 5.60 (s, 2H); 7.00 (m, 1H), 7.10–7.25 (m, 2H);7.25–7.45 (m, 4H); 7.65 (m, 1H); 8.25 (m, 1H); 8.90 (m, 1H), 8.97 (s,1H); 11.65 (brs, 1H).

Elemental Analysis

% calculated for C₂₀H₁₄FN₃O₃:

C=66.11, H=3.88, N=11.56, F=5.22

% found:

C=65.77, H=4,00. N=11.34, F=5.10.

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-(1H-tetrazol-5-yl)-acetamide

m.p. >270° C.

¹H-NMR (DMSO-d6, ppm): 5.60 (s, 2H); 7.10–7.25 (m, 2H); 7.25–7.48 (m,4H); 7.65 (m, 1H); 8.25 (m, 1H); 8.90 (s, 1H); 12.60 (br s, 1H).

Elemental Analysis:

% calculated for C₁₈H₁₃FN₆O₂:

C=59.34, H=3.60. F=5.21, N=23.07

% found:

C=59.12, H=3.64, F=5.12, N=22.59

2-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-2-oxo-N-[4H-(1,2,4)triazol-3-yl]-acetamide

m.p. >270° C.

Elemental Analysis:

% calculated for C₁₉H₁₄FN₅O₂:

C=62.81, H=3.88, N=19.27

% found:

C=62.50. H=3.94, N=18.78.

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide

m.p. 210–211° C.

¹H-NMR (DMSO-d6, ppm): 5.60 (s, 2H); 6.65 (m, 1H); 7.05–7.25 (m, 2H);7.25–7.48 (m, 4H); 7.60 (m, 1H); 7.75 (m, 1H); 8.98 (s, 1H); 12.75 (brs, 1H); 12.58 (br s, 1H).

N-(4-bromo-5-methyl-2H-pyrazol-3-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide

m.p. 198–200° C.;

1H-NMR (DMSO-d6, ppm): 2.20. (s, 3H); 5.60 (s, 2H); 7.10–7.25 (m, 2H);7.25–7.45 (m, 4H); 7.65 (m, 1H); 8.30 (m, 1H); 8.80 (s, 1H); 10.40 (br.s, 1H); 12.90 (br. s, 1H).

% calculated for C₂₁H₁₆BrFN₄O₂:

C=55.40. H=3.54, Br=17.55, N=12.31

% found:

C=55.82, H=3.75, Br=17.13, N=12.61.

N-(3,4-Dimethylisoxazol-5-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxoacetamide

m.p. 159–161° C.

¹H-NMR (DMSO-d6, ppm): 1.90 (s, 3H); 2.22, (s, 3H); 5.60 (s, 2H);7.10–7.25 (m, 2H); 7.25–7.48 (m, 4H); 7.65 (m, 1H); 8.30 (m, 1H); 8.93(s, 1H); 11.30 (br. s, 1H).

% calculated for C₂₂H₁₈FN₃O₃:

C=67.51, H=4.64, F=4.85, N=10.74

% found:

C=67.55, H=4.65, F=4.74, N=10.38.

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-[1,2,4-triazol-4-yl]-acetamide

m.p. 210–212° C.

¹H-NMR (DMSO-d6, ppm): 5.60 (s, 2H); 7.08–7.20 (m, 2H); 7.25–7.48 (m,5H); 7.65 (m, 1H); 8.30 (m, 1H); 8.80 (s, 1H); 9.03 (s, 1H); 12.50 (br.s, 1H).

% calculated for C₁₉H₁₄FN₅O₂:

C=62.81, H=3.88, F=5.23, N=19.27

% found:

C=62.46, H=4.01, F=4.90. N=18.1.

N-(4,5-dihydrothiazol-2-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide

m.p. 200–202° C.

¹H-NMR (DMSO-d6, ppm): 3.30 (t, 2H); 3.70 (t, 2H); 5.58 (s, 2H);7.08–7.45 (m, 6H); 7.60 (m, 1H); 8.25 (m, 1H); 8.55 (s, 1H); 10.20 (br.s, 1H).

% calculated for C₂₀H₁₆FN₃O₂S:

C=62.98, H=4.23, F=4.98, N=11.02, S=8.41

% found:

C=62.44, H=4.18, F=4.73, N=11.16, S=8.70.

N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-N-(1-methyl-4-oxo-4,5-dihydro-1H-pyrrol-2-yl)-2-oxo-acetamide

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-N-(1-methyl-2-oxo-1,2-dihydro-pyrimidin-4-yl)-2-oxo-acetamide

N-(2,6-dioxo-1,2,3,6-tetraidropyrimidin-4-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide

2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-(6-oxo-1,6-dihydro-pyrimidin-2-yl)-acetamide

2-[1-(4-Cyanobenzyl)-4-methyl-1H-indol-3-yl]-2-oxo-N-[1,3,4]thiadiazol-2-yl-acetamide

m.p. 203–205° C.

-   2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide;-   2-[1-(4-fluorobenzyl)-4-methyl-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide;-   2-[1-(4-chlorobenzyl)-6-fluoro-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide;-   2-[1-(3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide;-   2-[4-cyano-1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-(1H-pyrazol-3-yl)-acetamide;-   2-(1-(3,4-difluorobenzyl)-1H-indol-3-yl)-N-(isoxazol-3-yl)-2-oxo-acetamide;-   2-(4-methoxycarbonyl-1-(3,4-difluorobenzyl)-1H-indol-3-yl)-N-(isoxazol-3-yl)-2-oxo-acetamide;-   2-(6-chloro-1-(3,4-difluorobenzyl)-1H-indol-3-yl)-N-(isoxazol-3-yl)-2-oxo-acetamide;-   2-(1-(4-fluorobenzyl)-4-methyl-H-indol-3-yl)-N-(isoxazol-3-yl)-2-oxo-acetamide;-   N-(thiazol-2-yl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(thiazol-2-yl)-2-(6-fluoro-1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(thiazol-2-yl)-2-(4-methoxycarbonyl-1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(thiazol-2-yl)-2-(1-(3,4-difluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(thiazol-2-yl)-2-(1-(4-cyanobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(1,3,4-thiadiazol-2-yl)-2-(1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(1,3,4-thiadiazol-2-yl)-2-(1-(3-fluorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(1,3,4-thiadiazol-2-yl)-2-(6-bromo-1-(4-chlorobenzyl)-1H-indol-3-yl)-2-oxo-acetamide;-   N-(1,3,4-thiadiazol-2-yl)-2-(1-benzyl-1H-indol-3-yl)-2-oxo-acetamide;-   N-(benzimidazol-2-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(benzothiazol-2-yl)-2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(benzotriazol-1-yl)-2-[1-(3,4-difluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(5-bromopyrimidin-2-yl)-2-[1-(4-cyanobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(5-bromothiazol-2-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(4-ethoxycarbonylpyrazol-3-yl)-2-oxo-acetamide;-   N-(4-cyanopyrazol-3-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-benzyl-1H-indol-3-yl]-N-(3-cyano-4,5-dimethylfuran-2-yl)-2-oxo-acetamide;-   2-[1-(4-bromobenzyl)-1H-indol-3-yl]-N-(4,5-dimethylthiazol-2-yl)-2-oxo-acetamide;-   N-(5,6-dimethyl-1,2,4-triazin-2-yl)-2-[1-(3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(1,3-dimethyl-2,4-dihydro-2,4-dioxopyrimidin-6-yl)-2-[4-methyl-1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(1-ethylpyrazol-5-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-[1-(4-methylbenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(5-ethylthio-1,3,4-thiadiazol-2-yl)-2-[1-(4-methoxybenzyl)-1H-indol-3-yl]    2-oxo-acetamide;-   N-(5-hydroxypyrazol-3-yl)-2-[1-(4-methoxybenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(imidazol-2-yl)-2-[1-(4-trifluoromethylbenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(3,4-difluorobenzyl)-1H-indol-3-yl]-N-(isoquinolin-1-yl)-2-oxo-acetamide;-   N-(4-methoxy-6-methylpyrimidin-2-yl)-2-[1-(4-trifluoromethylbenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(1-methylbenzimidazol-2-yl)-2-oxo-acetamide;-   2-[1-(3,4-difluorobenzyl)-1H-indol-3-yl]-N-(3-methylisothiazol-5-yl)-2-oxo-acetamide;-   2-[1-(4-methoxybenzyl)-1H-indol-3-yl]-N-(5-methylisoxazol-3-yl)-2-oxo-acetamide;-   2-[1-(4-bromobenzyl)-1H-indol-3-yl]-N-(3-methylisoxazol-5-yl)-2-oxo-acetamide;-   2-[1-(4-cyanobenzyl)-1H-indol-3-yl]-N-(5-methylipyrazol-3-yl)-2-oxo-acetamide;-   2-[1-benzyl-1H-indol-3-yl]-N-(4-methylthiazol-2-yl)-2-oxo-acetamide;-   2-[6-fluoro-1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(5-methylthiazol-2-yl)-2-oxo-acetamide;-   2-[6-fluoro-1-(4-chlorobenzyl)-1H-indol-3-yl]-N-(5-nitrothiazol-2-yl)-2-oxo-acetamide;-   N-(5-phenylpyrazol-3-yl)-2-[4-methyl-1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-[1-(3-methoxycarbonylbenzyl)-1H-indol3-yl]-2-oxo-acetamide;-   N-(4-phenylthiazol-2-yl)-2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(pirazin-2-yl)-2-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(4-cyanopyrazol-3-yl)-2-[1-(3,4-dichlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   N-(pyrimidin-2-yl)-2-[1-(4-trifluoromethylbenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyrimidin-4-yl)-acetamide;-   N-(4-carboxymethylthiazol-2-yl)-2-[1-(4-chlorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(4-fluorobenzyl)-H-indol-3-yl]-2-oxo-N-(1,2,4-triazin-3-yl)-acetamide;-   N-(5-carboxy-1,2,4-triazol-3-yl)-2-[1-(3-fluorobenzyl)-1H-indol-3-yl]-2-oxo-acetamide;-   2-[1-(2-fluorobenzyl)-1H-indol-3-yl]-2-oxo-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-acetamide.

1. Compounds of formula (I)

wherein: HET is a four to seven membered heterocyclic group, aromatic ornon aromatic, containing one or more nitrogen, oxygen or sulfur atoms inone or more heterocyclic rings and optionally substituted on the carbonatoms with halogens, alkyl, hydroxy, alkoxycarbonyl, carboxy, cyanogroups or, on the nitrogen atoms, with alkyl, aryl, arylalkyl groups orwith oxygen atoms to form N-oxides; and optionally fused to one or twoaryl or cycloalkyl groups, in their turn optionally substituted withhalogens, alkyl, hydroxy, alkoxycarbonyl, carboxy, cyano groups; R₃ ishydrogen, C₁–C₄ alkyl, aralkyl, optionally substituted phenyl; R₄ isstraight or branched C₁–C₈ alkyl, C₅–C₆ cycloalkyl; aralkyl;heteroaralkyl; X represents one or more groups, up to four,independently selected from hydrogen, C₁–C₆ alkyl, hydroxy, C₁–C₄alkoxy, C₁–C₃ haloalkoxy, phenoxy, aralkoxy, C₁–C₃ acyloxy, amino, C₁–C₃alkylamino, C₁–C₃-acylamino, C₁–C₃-alkylsulfonylamino, aroylamino,halogen, nitro, cyano, trifluoromethyl, carboxy, C₁–C₃ alkoxycarbonyl, aR_(a)R_(b)N(CH₂)nC(═O)— group where R_(a) and R_(b) are independentlyhydrogen, C₁–C₃-alkyl or R_(a) and R_(b) together with the nitrogen atomthey are linked to form a pyrrolidino, piperidino, piperazino ormorpholino ring and n=0 or an integer 2 to 4, sulfonyl, mercapto,C₁–C₄-alkylthio, C₁–C₄-alkylsulfonyl, C₁–C₄-alkylsulfinyl,aminosulfonyl, C₁–C₃-alkylaminosulfonyl; with the proviso that HET isdifferent from aryl/heteroaryl substituted piperazine, or pyridine, orpyridine-N-oxide, and the pharmaceutically acceptable salts andtautomeric mixtures thereof.
 2. Compounds as claimed in claim 1 whereinHET is selected from pyrrole, furan, thiophene, pyrazole, thiazole,indole, oxazole, imidazole, isothiazole, isoxazole, 1,2,3-triazole,1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,5-oxadiazole,1,2,5-thiadiazole, 1,3,4-thiadiazole, tetrazole, pyrimidine, pyridazine,pyrazine, 1,2,4-triazine, benzofuran, indazole, carbazole, benzoxazole,benzimidazole, benzothiazole, benzotriazole, quinoline, isoquinoline,cinnoline, quinoxaline, quinazoline, phthalazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, purine, pteridine.
 3. Compounds asclaimed in claim 2 wherein HET is selected from pyrazole, isoxazole,thiazole, 1,3,5-thiadiazole.
 4. Compounds as claimed in claim 1 whereinR₃ is hydrogen or methyl.
 5. Compounds as claimed in claim 1 wherein R₄is methyl; benzyl substituted on the benzene ring with one or moregroups selected from methyl, fluorine, chlorine, bromine, hydroxy,methoxycarbonyl, ethoxycarbonyl, acetoxy, methoxy, trifluoromethoxy,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,methylmercapto, methysulfinyl, methylsulfonyl, phenyl; α-naphthylmethyl,β-naphthylmethyl; 4-pyridylmethyl; 4-pyridylmethyl N-oxide.
 6. Compoundsas claimed in claim 1 wherein X is methyl, ethyl, fluorine, chlorine,bromine, hydroxy, acetoxy, methoxy, phenoxy, trifluoromethoxy,trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino,methylmercapto, methysulfinyl, methylsulfonyl.
 7. Pharmaceuticalcompositions containing a compound of claim 1 in mixture with a suitablecarrier.